Regulatory aspects of continuous downstream processing

Over the past few years, various technologies have been developed to enable a partially or fully integrated continuous bioprocessing platform. Many companies have explored the potentials of these innovative production systems and a lot of data has been published that support the technical viability of integrated continuous bioprocessing. The regulatory agencies, such as the FDA, have repeatedly expressed their support for these developments as they recognize the potentials for enhanced process and product quality control. In addition to this, continuous bioprocessing may allow the industry to move towards a more agile state that would allow biopharmaceutical products to become available to a wider audience at lower costs. Even though the regulators are supportive, no guidance was provided in terms of the regulators’ for submissions and how the guidelines as summarized in ICH Q8 and Q9 can be applied in continuous bioprocessing. Many different companies working towards integrated continuous bioprocessing platforms, all of which are relying on a combination of innovative and existing technologies. In order to facilitate and harmonize the interactions with the regulatory bodies, we have developed strategies and approaches that would cover the typical regulatory aspects of integrated continuous manufacturing platforms, covering both upstream and downstream processing. In this presentation, we will present and discuss regulatory strategies for integrated continuous bioprocessing. This will cover critical quality attributes, bioburden control and virus safety strategies for continuous bioprocessing platforms. In addition to this, some aspects of traceability, lot definitions and deviation management will be addressed

Continuous downstream process development following quality by design philosophy

Continuous process technologies are available for essentially every step in a fully integrated continuous downstream processing platform. Most of these technologies have a significantly higher throughput and specific productivity than their batch equivalent process steps. The consequence is that the amount of material required to run experiments during continuous process development work is significantly higher than in batch process development. High throughput experimentation platforms have been established for performing design of experiments studies for many batch downstream processing steps, but for the equivalent continuous bioprocessing technologies this doesn’t exist. This limits the amount of different process variations that can be tested as part of the process characterization studies. In this presentation, we will analyze a continuous monoclonal antibody purification platform, using the Quality by Design approach to identify the key process parameters and critical process parameters. Based on the process knowledge and process design information available for the various continuous bioprocessing technologies, we will analyze how these critical process parameters translate into a continuous bioprocessing platform for monoclonal antibodies

Intensified bioprocessing enabling single-use technologies

more than a decade ago to the new state-of-the-art. The successful adoption of single use continues to be driven by the industry seeking for more flexible and cost-effective production platforms. In recent years, the rise of biosimilars and multiple drug entities becoming available for similar diseases has significantly increased the pressure on manufacturing costs. At the same time, production is more and more shifting towards smaller batches in highly flexible multiproduct facilities to adapt to the rapid and dynamically changing market demands. Driven by these needs, the industry has witnessed an upsurge of interest in intensified and continuous bioprocessing. Many companies are developing integrated continuous bioprocessing platforms by leveraging existing technology and combining it with novel, innovative single-use solutions. Intensified processing and single‑use technology thereby go hand-in-hand: continuous or intensified operation reduces the overall size of the manufacturing equipment which enables single-use technology in steps where the sheer size of an equipment has previously been a limiting factor. Instead of processing drug material as one single, large batch, an intensified platform moves the product through integrated unit operations either at a continuously low flow or in cycles of smaller sub-lots. Additionally, in intensified manufacturing, a carefully sized equipment enables producers to utilize it to produce various batch sizes and decrease the labor, costs, time and risks for up- or downscaling. A variety of fully continuous or hybrid batch/continuous manufacturing platforms for biologics have been created thus far, all of them predominantly based on single-use technologies. In these platforms, the focus of process intensification lies on four aspects: 1) the primary product flow, 2) the materials and buffer flow, 3) flow of information and 4) portability (scaling and Tech Transfer). A multitude of concepts and technologies have been successfully implemented to intensify the primary product flow, including perfusion upstream platforms, multicolumn chromatography systems, continuous virus inactivation and high-performance chromatography sorbents or membranes. In addition, the material and buffer preparations are a significant and often underrated contributor to process optimization. The recently developed single-use buffer management systems dilute process buffers from concentrates for the entire downstream platform both at point of use and just in time. Intensified processing has gained traction in the industry. Data from early adopters is promising, with first manufacturers moving their integrated platforms into cGMP environments. The ongoing adoption of intensified and continuous manufacturing concepts is enabling a more widespread use of single-use technology. In combination, the two concepts are a powerful and mutually enabling duo that may permit the biopharmaceutical industry to deliver essential drugs to larger patient populations at lower cost. Please click Additional Files below to see the full abstract

Process intensification - So much more than continuous bioprocessing

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Model assisted design of an intensified bioprocess

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Intensified bioprocessing: Data, data, everywhere...

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Природный и антропогенный факторы формирования и развития культурного ландшафта Форосского парка

Цель данной статьи: на примере небольшой территории Южного берега Крыма – парка в пгт. Форос и прилегающей к нему местности – показать роль и место культурного ландшафта в формировании человеком исторического геокультурного пространства

Efficacy and Tolerability of High- vs Low-Volume Split-Dose Bowel Cleansing Regimens for Colonoscopy: A Systematic Review and Meta-analysis

Background & Aims Efficacy of bowel preparation is an important determinant of outcomes of colonoscopy. It is not clear whether approved low-volume polyethylene glycol (PEG) and non-PEG regimens are as effective as high-volume PEG regimens when taken in a split dose. Methods In a systematic review of multiple electronic databases through January 31, 2019 with a registered protocol (PROSPERO: CRD42019128067), we identified randomized controlled trials that compared low- vs high-volume bowel cleansing regimens, administered in a split dose, for colonoscopy. The primary efficacy outcome was rate of adequate bowel cleansing, and the secondary efficacy outcome was adenoma detection rate. Primary tolerability outcomes were compliance, tolerability, and willingness to repeat. We calculated relative risk (RR) and 95% CI values and assessed heterogeneity among studies by using the I2 statistic. The overall quality of evidence was assessed using the GRADE framework. Results In an analysis of data from 17 randomized controlled trials, comprising 7528 patients, we found no significant differences in adequacy of bowel cleansing between the low- vs high-volume split-dose regimens (86.1% vs 87.4%; RR, 1.00; 95% CI, 0.98–1.02) and there was minimal heterogeneity (I2 = 17%). There was no significant difference in adenoma detection rate (RR, 0.96; 95% CI, 0.87–1.08) among 4 randomized controlled trials. Compared with high-volume, split-dose regimens, low-volume split-dose regimens had higher odds for compliance or completion (RR, 1.06; 95% CI, 1.02–1.10), tolerability (RR, 1.39; 95% CI, 1.12–1.74), and willingness to repeat bowel preparation (RR, 1.41; 95% CI, 1.20–1.66). The overall quality of evidence was moderate. Conclusions Based on a systematic review of 17 randomized controlled trials, low-volume, split-dose regimens appear to be as effective as high-volume, split-dose regimens in bowel cleansing and are better tolerated, with superior compliance

Fire resistance of circular concrete columns

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